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Amgen Inc. has developed an
antibody that mimics fibroblast
growth factor 21 and has antidiabetic effects in monkeys.1
The findings cap a year of advances that have greatly increased understanding
of the protein's tissue-specific actions, and work from groups including Eli Lilly and Co. and Roche's Genentech Inc. unit is informing
drug development by at least six companies.

Eli
Lilly scientists were the first to describe these functions in 2005 for the
protein,2 and the results prompted widespread industry interest in
the therapeutic potential of targeting the FGF21 pathway to treat type 2
diabetes and obesity.

David
Moller, VP of endocrine and cardiovascular research and clinical investigation
at Eli Lilly, told SciBX that the potential to simultaneously treat
multiple type 2 diabetes symptoms is the driving force behind pharma interest
in FGF21.

"One of our major strategic goals is to find a way
to treat the underlying disease pathophysiology in a way that can yield
multiple beneficial effects. That's what is exciting about the FGF21 pathway-there
is nothing else, practically speaking, that has the same effect."

Despite
the enticing functions, multiple hurdles have slowed the development of drugs
targeting the FGF21 pathway.3 Native FGF21 is not suitable as a drug
because of its short half-life. Development of drugs that mimic FGF21 function
has been difficult because the precise receptors, cell types and downstream
mechanisms responsible for the protein's beneficial effects need to be worked
out.

Junichiro
Sonoda, a scientist at Genentech, told SciBX that these unanswered
questions spurred intense industry and academic study of the pathway. "One
thing that really excites people about FGF21 is this novel biology. Nobody
knows exactly how FGF21 does all these fantastic things," he said.

Now,
Amgen and Genentech have built the case that FGFR
1c isoform (FGFR1c)
and KLB is the key complex and have shown antibodies designed to agonize the
target can mimic FGF21's therapeutic effect. Together with academic studies
describing essential pathways downstream of the receptor, a clearer picture of
FGF21 function has emerged that suggests a possible path forward to tap into
FGF21's therapeutic potential (see"FGF21
gets detailed").

The biotechs bookended 2012 with two
separate studies published in Science Translational Medicine that
described distinct FGF21-mimicking antibodies.

The first study was published in December 2011 by a
Genentech team led by Sonoda.5 The researchers identified an
antibody that could bind to and agonize FGFR1 (CD331) and tested it in a mouse model
of diabetes. The antibody lowered blood glucose compared with IgG control for
up to a month after a single injection and also caused weight loss.

The
effect was likely mediated by the antibody's action on adipose tissue, as mice
genetically engineered to lack the tissue did not show a reduction in blood
glucose when injected with the antibody.

Sonoda
told SciBX that it was a surprise that targeting FGFR1 alone could cause
such significant antidiabetic effects. "We knew FGF21 acts through the
liver, adipose tissue and potentially the pancreas, and FGF receptors were
expressed in different patterns in each tissue. It was really a surprise that
we could get this dramatic effect just by activating FGFR1 and not other FGF21
targets."

Despite
the promising efficacy, Genentech is not pursuing further development of this
antibody. Sonoda said the molecule binds FGFR1 but is not specific for the
FGFR1c and KLB complex, and widespread activation of a major growth factor
receptor could cause unpredictable side effects. Indeed, the antibody caused a
reduction in serum phosphate levels in mice.

Instead
of targeting FGF1R directly, Sonoda said the company would pursue the pathway
by specifically targeting FGFR1c and KLB.

Less
than 12 months later, a team at Amgen has published results showing the feasibility
of doing exactly that.1 By screening against the FGFR1c and KLB
complex, the company identified an antibody that specifically agonized FGFR1c
and KLB but not FGFR1c alone. In diabetic monkeys, the antibody caused weight
loss and decreased blood glucose and triglyceride levels compared with vehicle
control. The antibody had no significant effect on serum phosphate levels.

To
advance the argument that the FGFR1c and KLB complex in adipose tissue is
responsible for these effects, the team showed that FGF21 no longer reduced
blood glucose levels when administered to tissue-specific FGFR1 knockout mice.
These findings were in line with a study published by Eli Lilly in August 2012.6

"It
was a surprise that this antibody could activate a complex receptor structure. This
has never been seen before-there have been descriptions of agonistic
antibodies, but in this case it is a receptor complex. This is a special
antibody, and a major takeaway from the paper is that it opens up our eyes in
terms of thinking about what antibodies can do," said Yang Li, the
scientist at Amgen who led the team.

Amgen
has filed a patent covering antibodies targeting KLB and FGFRs, and the company
said that it is evaluating data from the current study and has not yet
determined next steps.

Safety
signals

Although the companies have shown proof of
concept that antibodies can mimic the positive metabolic effects of FGF21,
additional studies published in 2012 identified potential FGF21-mediated side
effects that will need to be monitored.

Last
February, a team at UT Southwestern Medical Center led by David Mangelsdorf and
Steven Kliewer published papers in Cell and the Proceedings of the
National Academy of Sciences that showed FGF21 can cause severe bone loss
in mice.7,8 The authors traced this effect to peroxisome proliferation-activated receptor-g (PPARG; PPARg), which they found is activated by
FGF21.

Mangelsdorf
told SciBX that these safety concerns are particularly worrisome given
the potential chronic administration of a diabetes drug. "This is not an
acute condition; these are hormones or compounds that you will put into people
for a long, long time, so the safety bar is a lot higher," he said. "FGF21
has some substantial side effects. The bone effect is really pronounced. It may
also suppress female reproduction, and there are going to be others."

Mangelsdorf
is chair of the Department of Pharmacology at UT Southwestern Medical Center
and an investigator of the Howard Hughes Medical Institute. Kliewer is a
professor of pharmacology at UT Southwestern Medical Center. He said his
results argue against developing long-acting forms of FGF21.

Long-acting
derivatives of FGF21 have been developed by multiple companies. Ambrx Inc. and partner Bristol-Myers Squibb Co. have ARX618, a pegylated form of FGF21, in
preclinical development.9 Amgen also has published work describing a
long-acting FGF21 analog, and Novo Nordisk A/S and Eli Lilly have filed patents
covering composition of matter on FGF21 derivatives.10

Mangelsdorf
said he sees more promise in the targeted approach presented by the Amgen team.
"If you can target the FGF21 pathway in a tissue-specific way, I think you
would have a drug," he said. He added that he would like to see the
tissue-specific effect of an FGFR1c and KLB antibody examined in more detail in
mouse models.

Jasbir
Seehra, CSO at Ember Therapeutics Inc., agreed that tissue-specific
targeting may be key to exploiting the tissue-specific effects of FGF21.

"While
this may be particular to mice, the potential for bone loss in humans will need
to be closely monitored in clinical studies. FGFR is expressed on cells in many
tissues, but KLB shows a restricted expression pattern in the pancreas, liver
and adipose tissue. In principle, an agonist antibody may be safer with limited
side effects because it targets only the tissues that express KLB," he
said.

Seehra
said Ember is evaluating the FGF21 pathway for therapeutics that could induce
brown fat-like properties, including increased glucose uptake and energy
expenditure. Earlier this year, FGF21 was shown by a team at Harvard Medical School to induce the
browning of white adipose tissue by activating the metabolic transcription
factor PPARG coactivator 1α (PPARGC1A; PGC-1α).11

Mangelsdorf
said this may explain how FGF21 is exerting its positive effects on metabolism.
"FGF21 is normally a starvation-induced hormone-it is a cry from the body
for energy. If you look at how it works in obese individuals, it acts on
adipose tissue to increase energy expenditure by stimulating glucose uptake and
inducing a thermogenic response."

Mangelsdorf's
team is continuing to uncover new physiological effects of FGF21. In October
2012, his team showed that mice engineered to constitutively overexpress FGF21
lived about 33% longer than wild-type mice, though these mice suffer bone loss
and females are infertile.12 The team is now trying to understand
pathways downstream of FGF21 that cause this effect on aging.

Genentech's
Sonoda said that the advances made in the last year are critical for
translating FGF21 to the clinic. "Every company that is working on this
pathway has to be aware of these findings. It is not clear to me yet whether
this approach would eliminate the safety liability of targeting the FGF21
pathway, but this is something we will need to work out with specific molecules."

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